Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5 to 10% of pregnancies and results in substantial maternal and fetal morbidity and mortality. Pre-eclampsia accounts for at least 200,000 maternal deaths worldwide per year. The symptoms of pre-eclampsia typically appear after the 20th week of pregnancy and are usually detected by routine measuring of the woman's blood pressure and urine. However, these monitoring methods are ineffective for diagnosis of the syndrome at an early stage, which could reduce the risk to the subject or developing fetus, if an effective treatment were available.
Currently there are no known cures for pre-eclampsia. Pre-eclampsia can vary in severity from mild to life threatening. A mild form of pre-eclampsia can be treated with bed rest and frequent monitoring. For moderate to severe cases, hospitalization is recommended and blood pressure medication or anticonvulsant medications to prevent seizures are prescribed. If the condition becomes life threatening to the mother or the baby the pregnancy is terminated and the baby is delivered pre-term.
The only known treatments for pre-eclampsia include anti-hypertensive therapy or delivery of the baby, which may jeopardize the health of the baby, the mother, or both.
The hallmarks of pre-eclampsia include hypertension, proteinuria, and edema. Placental maladaptation and body-wide endothelial cell dysfunction underlie these clinical manifestations. Failure of trophoblastic invasion into myometrial segments of maternal spiral arteries and the production of cytotoxic mediators which cause systemic endothelial damage also seem to be implicated. During normal development human trophoblasts invade through the extracellular matrix into the myometrial portion of spiral arteries and convert them into uteroplacental arteries. Uteroplacental arteries then dilate approximately 30-fold as large as the spiral arteries. The resulting hemodynamic changes enable the placental bed to satisfy the increased demand for oxygen from the fetus during the latter stages of gestation. In pre-eclamptic women, however, spiral arteries are not properly converted into uteroplacental arteries due to the failure of the second wave of trophoblastic migration into the myometrium at the beginning of the second trimester. As a result, pre-eclamptic women typically demonstrate a high-resistance, high-pressure, and low-flow state with intact, non-dilated spiral arteries, and demonstrate a wide variety of clinical syndromes.
Hypoxia refers to a condition in which the oxygen level is reduced below the normal physiological range. Hypoxic conditions have been shown to lead to increased sFlt-b 1 production by placental trophoblasts. sFlt-1 is a soluble form of the Flt-1 receptor, which is a receptor for VEGF and PlGF. Increases in sFlt-1 have been shown to be associated with pre-eclampsia, as have decreases in free VEGF and PlGF. Elevated levels of the soluble focus of the receptor can then bind to free VEGF and PlGF resulting in a decrease in the levels of these proteins. This imbalance in the levels and activity of these and other proteins is thought to be one of the contributing factors of pre-eclampsia or eclampsia.
All of the factors that contribute to the proper development of the fetus and the placenta have not yet been identified. There remains a need for the identification of the factors that are improperly regulated during pre-eclampsia and eclampsia. With such knowledge, methods of accurately diagnosing subjects at risk for or having pre-eclampsia or eclampsia, can be developed as well as therapeutic methods for the treatment and prevention of pre-eclampsia. It is therefore an object of the present invention to overcome these shortcomings in existing treatments for pre-eclampsia by providing safe and effective methods and compositions for the treatment of pre-eclampsia and other pregnancy related disorders.